The use of mechanical continuous infusion devices that will deliver insulin to diabetic patients within narrow dose tolerances for periods of one day to several weeks has been investigated extensively and reviewed in the literature [see, for example, Eaton, R. P., Diabetes Care 3:253-54, (1980); Prestele, K., Franetzki, M., and Kresse, H., Diabetes Care 3:362-68 (1980); Goriya, Y., Bahoric, A., Marliss, E. B., Zinman, B., and Albisser, A. M., Diabetes 28:558-64 (1980); Albisser, A. M., Botz, C. K., and Leibel, B. S., Diabetologia 16:129-33 (1979); Albisser, A. M., Proc. IEEE 67:1308-20 (1979); Santiago, J. V., Clemens, A. H., Clarke, W. L., and Kipins, D. M., Diabetes 28:71-84 (1979); A. M. Albisser, Diabetes Mellitus: Current and Future Therapies (M. Brownlee, ed.) Garland STPM Press, New York, Vol. 5:245-272, (1981); and Rizza, R. A., Gerich, J. E., Haymond, M. W., Westland, R. E., Hall, L. D., Clemens, A. H., and Service, J. F., New Engl. J. Med. 303:1313-18 (1980)]. "Open-loop" ambulatory pumps that deliver insulin by continuous infusion are commercially available, and implanted devices are being studied clinically [see, for example, Schade, D. S., Eaton, R. P., Edwards, W. S., Doberneds, R. C., Spencer, W. I., Carlson, G. A., Bair, R. E., Love, J. T., Urenda, R. S. and Gaona, J. I., J. Am. Med. Assoc. 247:1848-53 (l982); and Irsigler, K., Kritz, H., Hagmuller, G., Franetzki, M., Prestele, K., Thurow, H., and Geisen, K., Diabetes 30, 1072-75 (l981)]. Insulin delivery by continuous infusion devices carries a number of advantages relative to delivery by periodic bolus injections, the principal of which is that it permits the diabetic patient to maintain a more nearly normal glycemic and metabolic state and, thus, to experience an increased flexibility of lifestyle.
The insulin solution to be delivered by an infusion device is maintained in a reservoir, for example, a syringe, a synthetic polymeric bladder, a metal container, and the like. The reservoir and its associated pumping mechanism can be maintained externally or implanted in the patient. The insulin is delivered from the reservoir via small diameter catheters composed of synthetic polymeric materials.
A major problem encountered in delivering insulin by infusion systems is the tendency of insulin solutions over time to produce insulin aggregates, fibrils, or precipitates [see, for example, Lougheed, W. P., Woulfe-Flanagan, H., Clement, J. R., and Albisser, A. M., Diabetologia, 19:1-9 (l980)]. The aggregates and precepitates lead to obstruction of the catheter or pump components and the obstruction, in turn, to the interruption of the flow of insulin to the patient, resulting in poor glycemic control. Many factors have been implicated in the aggregation and precipitation of insulin in solution; however, those factors promoting aggregation and precipitation most likely to be encountered in all types of continuous infusion equipment are:
(a) elevated temperatures, e.g., 25.degree.-37.degree. C., as opposed to the usual 5.degree. C., storage conditions [Fisher, H. and Porter, P. B., Pharmaceut. Pharmacol. 33:203-06 (1980)]; PA1 (b) agitation, potentially caused by body movement or movement of pumping mechanisms [Irsigler, K., and Kritz, H., Diabetes 28:196-203 (1980)]; PA1 (c) association with an extended exposure of insulin molecules to hydrophobic surfaces, such as air interfaces and plastic or metal pump components [Weisenfeld et. al., Diabetes, 17, 766 (l968); and Browe et al., Eur. J. Biochem., 33, 233 (l973)]; and PA1 (d) outside stimuli, such as diffusion of CO.sub.2 through semi-permeable plastic or rubber components that cause the pH of insulin solutions to drift toward the isoelectric pH (pH 5.4) of insulin, where its solubility is very low [Lougheed et al., supra]. PA1 (a) sodium bicarbonate; PA1 (b) acidic insulin solutions [Schade, D. S., et. al. Satellite Symposium to 16th European Association for the Study of Diabetes Meeting, Greece, 22-23 Sept. l980, P. 107]; PA1 (c) acidic amino acids [Bringer, J., Heldt, A., and Grodsky, M., Diabetes 30: 83-85 (l981)]; PA1 (d) non-polar and non-aqueous solvents; PA1 (e) calcium and magnesium ions [Havelund, Jorgen, and Grange, U.K. Patent Application No. GB2094145A]; PA1 (f) ionic surfactants [Lougheed et al., supra]; and PA1 (g) non-ionic surfactants [German Patent Application P2959119.5; and Henry, M., McMullen, J. K., Grant, H. P., and Tindall, C. E., Irish Journal of Medical Science, 230 (l982)].
The principal approach for preventing or delaying insulin-related obstructions in infusion devices has been to modify insulin preparations by addition of an "anti-aggregation" stabilizer. Several additives or kinds of additives have been proposed as solutions to the aggregation problem. Among these are:
Each of the above reagents or classes is perhaps useful under certain well-defined and limited conditions. The deficiency of each as a general class, however, is that it protects insulin from aggregation or precipitation caused by only one or less than all of the several possible mechanisms. It is probable that all factors implicated in the obstruction of insulin infusion systems are operative during actual use of infusion devices, or, if all are not operative in any selected isolated use of an infusion device, all certainly are cumulatively present in the wide range of conditions under which infusion devices are used.
Sodium bicarbonate and acidic anti-aggregation stabilizers, for example, prevent isoelectric precipitation of insulin; they are not, however, effective in protecting insulin from agitation-induced aggregation (denaturation) or temperature-induced fibril formation. Moreover, acidic insulin solutions degrade rapidly.
Ionic and non-ionic surfactants, whether physiologic or synthetic, are recognized to reduce the propensity of insulin to precipitate from solution by mechanical stress or surface interactions [U.S. Pat. 4,120,560; European Patent Application No. 80102252.6]. It has also been reported that a synthetic non-ionic polyethylene-polypropylene glycol surfactant, Pluronic Polyol F-68, is effective in eliminating precipitation of protein from a horse serum-containing medium used in mechanically-shaken tissue culture [Swim et al., Proc. Soc. Exp. Bio. Med. 103, 252 (l960)].
The recognized protein-solvation characteristics of surfactants and their potential for maintaining insulin conformation [Wu, C-S. C., and Yang, J. T., Biochem. Biophys. Acta 667:285-93 (l981)] makes them recognized as likely candidates as insulin anti-aggregation stabilizers. Notwithstanding this fact, surfactants would not be expected to inhibit aggregation and precipitation caused by other factors, e.g., pH drift.
The present invention defines novel insulin formulations having substantially delayed insulin aggregation or precipitation properties. The insulin formulations of this invention contain a selected polypropylene-polyethylene glycol surfactant in combination with a phenol. The insulin formulations of the invention, containing the selected polypropylene-polyethylene glycol and a hydroxybenzene, exhibit a surprising and unexpectedly high retardation of insulin aggregation. It was further discovered that insulin formulations containing the selected polypropylene-polyethylene glycol but lacking a hydroxybenzene showed only a mild protective effect against insulin aggregation and precipitation, and, moreover, that those formulations containing a hydroxybenzene but none of the selected polypropylene-polyethylene glycol actually hastened insulin aggregation.